is produced by endothelial and proximal tubule cells. With acidosis, ET-1 secretion is enhanced. In the proximal tubule, ET-1 stimulates phosphorylation and subsequent insertion of the Na+/H+ antiporter into the apical membrane, and insertion of the Na+/3HCO3 − symporter into the basolateral membrane. ET-1 may mediate the response to acidosis in other nephron segments as well. Acidosis also stimulates secretion of the glucocorticoid hormone cortisol by the adrenal cortex. Cortisol increases the abundance of the Na+/ H+ antiporter and Na+/3HCO3 − symporter in the proximal tubule. Angiotensin II is produced in proximal tubule cells in response to acidosis. It is secreted into the tubular fluid, where it binds to the angiotensin I receptor and thereby stimulates H+ secretion/HCO3 − reabsorption by the proximal tubule. Both cortisol and angiotensin II also stimulate production and secretion of NH4 + by the proximal tubule, which as described later is an important component of the kidney’s response to acidosis.
Acidosis also stimulates secretion of parathyroid hormone (PTH). PTH inhibits phosphate (Pi) reabsorption by the proximal tubule (see ). In so doing, more Pi is delivered to the distal nephron, where it serves as a urinary buffer and thus increases the capacity of the kidneys to excrete titratable acid.
The response of the kidneys to alkalosis is less well characterized. RNAE is decreased because of increased urinary HCO3 − excretion and because excretion of titratable acid and NH4 + are reduced. The factors that regulate this response are not well characterized.
Other factors not necessarily related to maintaining acid-base balance can influence secretion of H+ by the cells of the nephron. Because a significant H+ transporter in the nephron is the Na+/H+ antiporter, factors that alter Na+ reabsorption can secondarily affect H+ secretion. For example, with volume contraction (negative Na+ balance), Na+ reabsorption by the nephron is increased (see ), including reabsorption of Na+ via the Na+/H+ antiporter. As a result, H+ secretion is enhanced. This occurs by several mechanisms. One mechanism involves the renin-angiotensinaldosterone system, which is activated by volume contraction. As noted earlier, angiotensin II acts on the proximal tubule to stimulate the apical membrane Na+/H+ antiporter as well as the basolateral Na+/3HCO3 − symporter. To a lesser degree, angiotensin II stimulates H+ secretion in the TAL of Henle’s loop and the early portion of the distal tubule, a process also mediated by the Na+/H+ antiporter. Aldosterone’s primary action on the distal tubule and collecting duct is to stimulate Na+ reabsorption by principal cells (see ). However, it also stimulates intercalated cells in these segments to secrete H+ . This effect is both indirect and direct. By stimulating Na+ reabsorption by principal cells, aldosterone hyperpolarizes the transepithelial voltage (i.e., the lumen becomes more electrically negative). This change in transepithelial voltage then facilitates secretion of H+ by intercalated cells. In addition to this indirect effect, aldosterone (and angiotensin II) act directly on intercalated cells to stimulate H+ secretion via H+-ATPase and H+,K+-ATPase.
Another mechanism by which ECF volume (ECFV) contraction enhances H+ secretion (HCO3 − reabsorption) is through changes in peritubular capillary Starling forces. As described in , ECFV contraction alters the peritubular capillary Starling forces such that overall proximal tubule reabsorption is enhanced. With this enhanced reabsorption, more of the filtered load of HCO3 − is reabsorbed.